Abstract Dopaminergic mechanisms, particularly the function of the nigrostriatal pathway, are strongly implicated in dystonia. Clinical studies and postmortem studies have shown reductions in dopamine receptor ligand binding. Acute treatment with dopamine antagonists can induce dystonia in normal individuals. Studies in animal models have shown diminished extracellular striatal dopamine and impaired dopamine release in response to sympathomimetic agents. Genetic defects in dopamine synthesis can also cause dystonia, and these rare forms often respond to dopamine replacement. In most forms of dystonia, however, simple dopamine replacement treatments are ineffective. From a clinical perspective, the most effective medications available for dystonia are anticholinergic drugs. These non-selective muscarinic receptor antagonists are clinically effective but produce a range of anticholinergic side effects and are not well tolerated. Studies in mouse models of DYT1 dystonia have provided experimental support for the concept that dystonia may be related to abnormalities of cholinergic transmission, with downstream effects on dopamine release and synaptic plasticity in the striatum. We have found that animals with transgenic expression of mutant torsinA have profound abnormalities of cholinergic neuron function, with paradoxical excitation in response to dopamine D2 activation. These same effects are reproduced in animals with selective deletion of torsinA from cholinergic cells, demonstrating that the effect is at least in part cell autonomous. Recently, two additional genes causing dystonia have been discovered by our P01 collaborators: mutations in the transcription factor THAP1 and heterozygous deletion of GNAL, encoding the G?olf regulatory G protein. All three genes produce a similar phenotype. Mechanistically, these may be related in that THAP1 may regulate torsinA expression and abnormal G protein signaling seems to be a downstream consequence of torsinA dysfunction. Our central hypothesis is that abnormal cholinergic function and downstream signaling is responsible for abnormal striatal signaling in dystonia, and that selective modulation of muscarinic and nicotinic receptors can normalize striatal physiology. We will explore this in mouse models of these three forms of genetic dystonia. Our studies will determine if DYT1, THAP1, and GNAL dystonia share common cholinergic mechanisms, whether this leads to disrupted dopaminergic function, and whether these abnormalities can be reversed by modulation of the cholinergic system and by modulation of downstream signaling. We incorporate studies of a novel series of cholinergic antagonists and modulators which provide a potential pathway to translate these findings into therapies for human dystonias.